Fine-Scale Regulation of Notch Signalling Dynamics: in the Context of Vertebrate Segmentation Clock

在发育过程中，细胞分裂并承担不同的命运，以形成组织，这些组织以高度协调的方式生长并形成图案，形成身体器官。这种协调的丧失导致出生缺陷和/或癌症。这种协调依赖于发育中的胚胎细胞之间高度复杂和严格调控的通信。这种通信是由分子信号传导途径促进的，细胞通过分子信号传导途径向彼此发送分子信号并相应地做出反应。我们将研究这集中在一个器官的发展;分段的骨骼，所有脊椎动物物种的特征。调节细胞分裂并指导细胞采取特定命运的主要信号传导途径之一，最终导致整个发育过程中正确的组织形成，这是Notch信号传导途径，我们和其他人已经证明这是分割所必需的。当该途径被激活时，NOTCH蛋白的一个片段，称为“NICD”被释放并打开其他靶基因。随后，NICD被销毁。当这个“关闭”开关出现故障时，通路被激活得太强，导致许多癌症。如何控制该“关闭”开关的细节尚不清楚。我们的目标是确定如何控制NICD的水平，以及如何协调骨骼发育。这对于“关闭“开关有故障的疾病背景将是非常有用的。

During development, cells divide and take on different fates to make tissues that grow and become patterned to form body organs in a highly co-ordinated fashion. Loss of this co-ordination leads to birth defects and/or cancer. This co-ordination relies on highly sophisticated and tightly regulated communication between cells in the developing embryo. This communication is facilitated by molecular signalling pathways whereby cells send molecular signals to one another and respond accordingly. We will investigate this focussing on development of one organ; the segmented skeleton, a feature of all vertebrate species. One of the major signalling pathways that regulates cell division and directs cells to take on specific fates which ultimately leads to correct tissue formation throughout development is the Notch signalling pathway which we and others have shown is essential for segmentation. When the pathway is activated, a fragment of NOTCH protein, called "NICD" is released and switches on other target genes. Subsequently, NICD is destroyed. When this "off" switch is faulty the pathway is activated too strongly which causes numerous cancers. The details of how this "off" switch is controlled is not known. We aim to determine how the level of NICD is controlled, and how this co-ordinates skeletal development. This will be very informative to disease contexts where the "off "switch is faulty.